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Patent 2462075 Summary

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(12) Patent Application: (11) CA 2462075
(54) English Title: ESTROGEN/GESTAGEN COMBINATION PREPARATION AND APPLICATION THEREOF
(54) French Title: PREPARATION D'ASSOCIATION ESTROGENE-PROGESTATIF ET SON UTILISATION
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61K 31/565 (2006.01)
  • A61J 1/14 (2006.01)
  • A61J 7/04 (2006.01)
  • A61K 31/56 (2006.01)
  • A61K 31/566 (2006.01)
  • A61K 31/567 (2006.01)
  • A61K 31/57 (2006.01)
  • A61K 31/58 (2006.01)
  • A61P 5/30 (2006.01)
  • A61P 5/34 (2006.01)
  • A61P 15/00 (2006.01)
  • A61P 15/12 (2006.01)
  • A61K 35/22 (2006.01)
(72) Inventors :
  • SCHWANITZ, DIETHARD (Germany)
  • ROGOLL, JUTTA (Germany)
  • HACHMEISTER, BERND (Germany)
(73) Owners :
  • SCHWANITZ, DIETHARD (Not Available)
  • ROGOLL, JUTTA (Not Available)
  • HACHMEISTER, BERND (Not Available)
(71) Applicants :
  • SOLVAY PHARMACEUTICALS GMBH (Germany)
(74) Agent: NORTON ROSE FULBRIGHT CANADA LLP/S.E.N.C.R.L., S.R.L.
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2002-09-25
(87) Open to Public Inspection: 2003-04-10
Examination requested: 2004-03-26
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/EP2002/010728
(87) International Publication Number: WO2003/028735
(85) National Entry: 2004-03-26

(30) Application Priority Data:
Application No. Country/Territory Date
01123511.6 European Patent Office (EPO) 2001-09-29

Abstracts

English Abstract




The invention relates to novel estrogen/gestagen combination preparations for
application in hormone replacement therapy, for example, for application in
menopausal or climacteric complaints.


French Abstract

La présente invention concerne de nouvelles préparations d'association estrogène-progestatif destinées à être utilisées dans le traitement hormonal substitutif, par exemple, dans les plaintes relatives à la ménopause.

Claims

Note: Claims are shown in the official language in which they were submitted.





15

Claims

1. Use of an estrogen and a gestagen for production of an oral
pharmaceutical preparation which contains 14 separate daily dosage
units (or an integral multiple thereof) of an estrogen active
ingredient and a corresponding number of a combination of an estrogen
active ingredient with a gestagen active ingredient in combined daily
dosage units for the prevention, relief and/or treatment of menopausal
symptoms in women, in particular in women with an intact uterus, when a
menstrual cycle is no longer desired, by daily alternating
uninterrupted administration of the daily dosage units of the estrogen
active ingredient and the combined daily dosage units of the
combination of the estrogen active ingredient with the gestagen active
ingredient over a period of at least 28 days (28-day cycle).

2. Use as claimed in Claim 1, characterized in that the
pharmaceutical preparation contains 14 daily dosage units of an
estrogen active ingredient on the one hand and 14 daily dosage units of
a combination of the estrogen active ingredient with a gestagen active
ingredient on the other hand for a 28-day cycle or triple the number of
daily dosage units of an estrogen active ingredient on the one hand and
the combination of the estrogen active ingredient with a gestagen
active ingredient on the other hand as required for a 28-day cycle.

3. Use as claimed in any one of the preceding claims,
characterized in that the estrogen active ingredient is selected from
the group consisting of estradiol, 17.beta.-estradiol, estradiol valerate,
natural conjugated estrogens including those of equine origin, estrone,
estropipate (piperazine estrone sulfate), ethinyl estradiol, mestranol
and quinestranol, preferably natural conjugated equine estrogens.

4. Use as claimed in any one of Claims 1 and 2, characterized
in that the gestagen active ingredient is selected from the group
consisting of levonorgestrel, dl-norgestrel, norethindrone
(norethistrone), norethindrone (norethistrone) acetate, ethynodiol
diacetate, dydrogesterone, medroxyprogesterone acetate, norethynodrel,
allylestrenol, lynoestrenol, quingestanol acetate, medrogestone,
norgestrienone, dimethisterone, ethisterone, cyproterone acetate,




16

chlormadinone acetate, megestrole acetate, gestoden, desogestrel,
trimegestone, dienogest, drosperinone and nomegestrole acetate,
preferably from the group of dydrogesterone, medroxyprogesterone
acetate, norethistrone acetate, trimegestone, dienogest, drosperinone
and especially medrogestone.

5. Use as claimed in any one of the preceding claims,
characterized in that the estrogen active ingredient consists of a
mixture of natural conjugated equine estrogens in an amount of 0.05 mg
to 10 mg, depending on the type of estrone used, in a daily dosage unit
of the estrogen active ingredient, and in the combined daily dosage
unit the estrogen active ingredient, preferably also a mixture of
natural conjugated equine estrogens, is present in an amount of 0.05 mg
to 10 mg, depending on the type of estrone used, and the gestagen
active ingredient is used in an amount of 0.05 mg to 50 mg, depending
on the gestagen used, preferably the medrogestone that is preferred as
the gestagen active ingredient is present in an amount of 1 mg to
20 mg, in particular in an amount of 1 mg to 10 mg.

6. Use as claimed in Claim 5, characterized in that the daily
dosage unit of the estrogen active ingredient contains 14 mg of an
extract from the urine of gravid mares, standardized to 0.33 mg sodium
salt of estrone 3-hydrogen sulfate and 0.17 mg sodium salt of equiline
3-hydrogen sulfate (corresponding to 0.6 mg conjugated equine
estrogens), and the combined daily dosage unit contains a combination
of 14 mg of an extract from the urine of gravid mares, standardized to
0.33 mg sodium salt of estrone 3-hydrogen sulfate and 0.17 mg sodium
salt of equiline 3-hydrogen sulfate (corresponding to 0.6 mg conjugated
estrogens) as the estrogen active ingredient and 5 mg medrogestone as
the gestagen active ingredient.

7. Packaged pharmaceutical preparation for hormone replacement
therapy containing
- a packaging material in which 14 daily dosage units (or an integral
multiple thereof) of an estrogen active ingredient and the
corresponding number of a combination of an estrogen active
ingredient with a gestagen active ingredient in combined daily




17


dosage units are accommodated separately, and the daily doses of the
estrogen active ingredient on the one hand and the combined daily
doses of the estrogen active ingredient and the gestagen active
ingredient on the other hand are suitably labeled and/or
characterized to clearly differentiate them from one another, and
- a label and/or a package insert to indicate that the preparation may
be administered for the prevention, relief and/or treatment of
menopausal symptoms in women, especially in women with an intact
uterus when a menstrual cycle is no longer desirable, by
uninterrupted daily administration of the daily dosage units,
alternating each day, of the estrogen active ingredient and the
combined daily dosage units of the combination of the estrogen
active ingredient with the gestagen active ingredient over a period
of at least 28 days (28-day cycle).

8. Packaged pharmaceutical preparation as claimed in Claim 7,
characterized in that the daily dosage unit containing the estrogen
active ingredient on the one hand and the daily combined daily dosage
unit of estrogen active ingredient and gestagen active ingredient on
the other hand are labeled by optical labeling, preferably by different
colors, for differentiation from one another.

9. Packaged pharmaceutical preparation as claimed in Claim 7,
characterized in that the packaging material is a blister pack on which
is printed a schedule to facilitate alternating administration of the
daily dosage units of the estrogen active ingredient and the combined
daily dosage unit of the estrogen active ingredient and gestagen active
ingredient, preferably printed out as a diagram of integers from 1 to
28.

10. Packaged pharmaceutical preparation as claimed in Claim 7,
characterized in that the packaging material [includes] a pill
dispenser which is subdivided into 28 compartments, preferably a pill
dispenser which is subdivided into 28 compartments and has a ring-
shaped arrangement of these compartments in which a daily dosage unit
of estrogen active ingredient and a combination daily dosage unit of
estrogen active ingredient and gestagen active ingredient are




18


accommodated in alternation and are labeled to differentiate them from
one another clearly.

11. Packaged pharmaceutical preparation as claimed in Claim 9,
characterized in that the blister pack additionally has a second cyclic
scheme provided on the opposite side in addition to the scheme for
alternating administration of the daily dosage units of estrogen active
ingredient on the one hand and the combined daily dosage unit of
estrogen active ingredient and gestagen active ingredient on the other
hand, specifying the use of initially 14 daily dosage units of the
estrogen active ingredient, which are then followed by 14 combined
daily dosage units of estrogen active ingredient and gestagen active
ingredient for women in whom a menstrual cycle is still desirable.


Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02462075 2004-03-26
Estrogen/Gestagen Combination Preparation and Application Thereof
Description
The present invention relates to novel estrogen-gestagen
combination preparations for use in hormone replacement therapy, e.g.,
for use in treating menopausal symptoms.
Typical menopausal symptoms occur in conjunction with menopause
in women. With the onset of menopause, the ovaries gradually begin to
stop functioning so the formation of the female sex hormones estrogen
and progesterone declines and ultimately stops entirely. Reproductive
ability disappears. The decline in hormone production is associated
with numerous changes in the female body which may be manifested in
menopausal symptoms, aging of the skin, a decline in bone mass, an
increased risk of cardiovascular diseases and a gradual loss of
intellectual ability.
To prevent, relieve and/or treat menopausal symptoms, hormone
replacement therapy is generally prescribed to act in the body instead
of the hormones that are no longer supplied by the ovaries. Hormone
preparations, e.g., in the form of pills with an estrogen active
ingredient are used in the state of art as monopreparations and as
combination preparations with a gestagen as an additional active
ingredient.
Depending on the patient and the type of combination preparation, the
estrogen active ingredient and the gestagen active ingredient may be
administered cyclically or continuously, by oral administration of
effective dosage units of the hormone active ingredients, usually in
regimens without interruption, but optionally also with interruption
phases. In a combination preparation currently on the market, the
dosage is administered with single and daily doses by oral
administration of one pill containing estrogen from days 1 through 14
of the cycle (in women who still have a menstrual cycle) and by oral
administration of one pill daily containing a combination of estrogen
active ingredient and gestagen active ingredient from days 15 to 28 of
the cycle. Another pharmaceutical combination preparation of the state


CA 02462075 2004-03-26
2
of the art is described in European Patent Application EP 136011 B1.
EP 136011 B1 proposes therapeutic combination preparation with low-dose
gestagen and estrogen active ingredients for treatment of
postmenopausal symptoms in women with an intact uterus; this treatment
regimen includes 20 to 120 combined dosage units of gestagen and
estrogen plus if desired 3 to 7 separate daily gestagen dosage units
(not containing estrogen). These preparations may be administered first
by continuous uninterrupted oral administration of gestagen and
simultaneous continuous uninterrupted oral administration of estrogen
once a day in the form of a single combined dosage unit of the two
hormones. On the other hand, estrogen may also be administered
cyclically in an oral dose, with the gestagen and estrogen initially
being administered for 20 to 120 days once daily in the form of the
combined dosage unit and gestagen being administered once a day for 3
to 7 days in the form of the gestagen dosage units.
Menopausal symptoms are often perceived very differently by the
individual women affected. The choice of an individual regimen for the
prevention, relief and/or treatment of menopausal symptoms therefore
makes a flexible possibility for variation of treatment seem desirable,
i.e., a treatment regimen that would optionally also allow alternative
use regimen with one and the same preparation.
Therefore the present invention proposes a novel estrogen-
gestagen combination preparation with an alternating regimen. Therefore
this invention relates to the use of an estrogen and a gestagen for
producing an oral pharmaceutical preparation which contains separate
daily dosage units (14 or multiple thereof) of an estrogen active
ingredient and a corresponding number of a combination of an estrogen
active ingredient with an gestagen active ingredient in combined daily
dosage units, for the prevention, relief and/or treatment of menopausal
symptoms in women, in particular in women with an intact uterus, if a
menstrual cycle is no longer desired, by daily alternating
uninterrupted administration of the daily dosage units of the estrogen
active ingredient and to combined daily dosage units of the combination
of the estrogen active ingredient with the gestagen active ingredient
over a period of at least 28 days (28-day cycle).


CA 02462075 2004-03-26
3
The inventive pharmaceutical preparation is suitable for the
prevention, relief and/or treatment of menopausal symptoms including
pre-, peri- and postmenopausal symptoms in women with an intact uterus
when a menstrual cycle is no longer desired. Menopausal symptoms here
include a number of adverse effects or pathological changes because of
the changing hormone balance. Perimenopausal women (e. g., approximately
those more than 40 years of age), menopausal and postmenopausal women
often suffer a variety of different states and symptoms which are to be
attributed to withdrawal from estrogen because of subsiding function of
the ovaries. Such symptoms may vary greatly in duration and they may be
manifested, for example, in hot flashes of varying extent, depending on
the individual, and in vaginal dryness with an increased susceptibility
to infections. The bone mineral loss in particular is associated with a
decline in bone mass (osteoporosis) as a long-term menopausal,
perimenopausal and postmenopausal condition that is very threatening to
a woman's health. In addition, an increased risk of heart attacks and
ischemic heart disease due to definitely elevated serum cholesterol
levels has also been discussed in the professional medical world. In
some women, other symptoms such as depression, insomnia, nervousness or
even such conditions as arthritis, etc., may occur in addition to the
main symptoms and pathological states mentioned above.
In treatment of menopausal, perimenopausal and postmenopausal
symptoms, it is acknowledged that estrogen is the most effective agent
for controlling hot flashes and vaginal atrophy and it prevents or
retards the occurrence of clinical manifestations of osteoporosis. From
a clinical standpoint it is not necessary to administer estrogens alone
but instead they are preferably administered in combination with a
gestagen in a suitable dosage and/or treatment regimen. The present
invention here makes available a combination and type of administration
not previously known in the related art for this purpose.
The indications according to the present invention include in
particular premenopausal and menopausal symptoms with menstrual
disorders, menstrual irregularities (menstrual anomalies), lack of
menstrual bleeding (amenorrhea), too little menstrual bleeding
(hypomenorrhea), too infrequent menstrual bleeding (oligomenorrhea),


CA 02462075 2004-03-26
4
excessive menstrual bleeding (hypermenorrhea), spotting between periods
and inadequate functioning of the ovaries (ovarian insufficiency).
The preparation according to this invention is administered in an
alternating treatment regimen with individual doses and daily doses.
This alternating therapy regimen is suitable in particular for the
group of patients who no longer wish to have a menstrual cycle. The
gestagen is administered here in alternation, as can be seen from FIG 1
in an exemplary embodiment of this invention, for example. For example
if the estrogen active ingredient is formulated in white pills and the
estrogen-gestagen combination is formulated in pink pills, then the
alternating administration of gestagen is done by administering one
white and one pink pill in alternation each day. In other words, on the
first day a white pill (1) is taken, on the second day a pink pill (2)
is taken, on the third day a white pill (3) is taken again and on the
fourth day a pink pill (4) is taken again, etc., until reaching the end
of a 28-day cycle.
With this alternating dosage regimen (pink-white regimen), the
pills are to be taken in the order of the numbers given, beginning with
the number (1) according to a treatment regimen which is printed on the
front of a blister pack strip, for example, as shown in FIG 1. These
numbers do not indicate the date but instead indicate the sequence in
which the particular pills are to be taken. Other example of
embodiments for the arrangement and labeling of the particular pills in
inventive forms of administration for the alternating treatment regimen
are depicted in FIG 3 and FIG 4. Inventive packaged pharmaceutical
preparations suitable for this purpose are described in greater detail
below.
If the patient is having regular menstrual periods before the
beginning of the treatment or when changing to this dosage regimen, the
first dose of the medication is begun on day one of menstruation. Women
who no longer have a uterus or who are no longer having menstrual
periods can begin taking the medication at any time.
After consuming the entire blister pack, i.e., after completing a
28-day cycle, the next pill is taken on the following day, i.e.,
without a pause, starting with a new blister pack according to the same


CA 02462075 2004-03-26
alternating pink-white regimen as that described above, following the
numbers used for orientation purposes.
To facilitate use of the medication, the pills may also be
presorted in a pill dispenser, always alternating pink and white for
one month (28-day cycle). To explain this aspect of the invention, FIG
5A and FIG 5B give an example of the geometric design of a pill
dispenser or pill dispenser, i.e., a pill dispenser having a round
geometry; other geometric designs, e.g., oval shapes or rectangular
shapes are also possible, e.g., by analogy with the blister packs. In
addition, this aspect of the invention is described in greater detail
below in conjunction with the pharmaceutical preparations packaged
according to this invention.
In a preferred variant of this invention, the pharmaceutical
preparation includes 14 daily dosage units of an estrogen active
ingredient and 14 daily dosage units of a combination of the estrogen
active ingredient with a gestagen active ingredient. This
pharmaceutical preparation consisting of 14 daily dosage units of each
is intended for a one-month treatment, i.e., a 28-day cycle and is
packaged accordingly. If desired, the inventive pharmaceutical
preparation may also be intended for three months of treatment, i.e.,
for three successive 28-day cycles and packaged accordingly, i.e., the
three times the number of daily dosage units required for a 28-day
cycle is made available, each dosage unit containing the estrogen
active ingredient on the one hand and the combination of the estrogen
active ingredient with a gestagen active ingredient on the other hand.
In this three-month variant, the pharmaceutical preparation then
includes, for example, three separate package subunits of 14 daily
dosage units of an estrogen active ingredient and 14 daily dosage units
of a combination of the estrogen active ingredient with a gestagen
active ingredient or, for example, three times 14 daily dosage units of
an estrogen active ingredient and three times 14 daily dosage units of
a combination of the estrogen active ingredient with a gestagen active
ingredient. As an alternative, 42 daily dosage units of an estrogen
active ingredient and 42 daily dosage units of a combination of the
estrogen active ingredient with a gestagen active ingredient may also
be provided for the three-month variant.


CA 02462075 2004-03-26
6
Estrogens that can be used within the scope of this invention
include estrogen active ingredients selected from the group consisting
of estradiol, 17a-estradiol, estradiol valerate, natural conjugated
estrogens including those of equine origin, estrone, estropipate
(piperazine estrone sulfate), ethinyl estradiol, mestranol and
quinestranol. Natural conjugated equine estrogens (CEE - conjugated
equine estrogens) are preferred. Natural conjugated estrogen hormones
are an amorphous extract representing mixtures of water-soluble
conjugated estrogens usually obtained from natural sources such as in
particular the urine of gravid mares. The main estrogenic component in
this mixture is the sodium salt of estrone sulfate and, in a lesser
amount, the sodium salt of equiline sulfate. The total estrogenic
efficacy of pharmaceutical preparations is usually expressed in the
form of equivalent amounts of the sodium estrone sulfate salt and
optionally the sodium equiline sulfate salt. Other conjugated
estrogenic active ingredient components present in the mixtures of
natural conjugated estrogens are also present as water-soluble sodium
sulfate salts in the mixtures including for example 17a-dihydroquiline,
17a-estradiol and 17a-dihydroequiline. Tablets for oral administration
contain mixtures of the natural conjugated estrogens, usually in
amounts of approximately 0.3 mg, 0.625 mg, 0.9 mg, 1.25 mg and 2.5 mg
of the conjugated estrogens.
Gestagens that can be used within the scope of this invention
include gestagen active ingredients selected from the group consisting
of levonorgestrel, dl-norgestrel, norethindrone (norethistrone),
norethindrone (norethistrone) acetate, ethynediol diacetate,
dydrogesterone, medroxyprogesterone acetate, norethynodrel,
allylestrenol, lynoestrenol, quingestanol acetate, medrogestone,
norgestrienone, dimethisterone, ethisterone, cyproterone acetate,
chlormadinone acetate, megestrole acetate, gestoden, desogestrel,
trimegestone, dienogest, drosperinone and nomegestrole acetate.
Gestagens that are preferred according to this invention include
dydrogesterone, medroxyprogesterone acetate, norethistrone acetate,
trimegestone, dienogest, drosperinone and in particular medrogestone.
In one embodiment of this invention, the daily dosage unit of
estrogen contains the estrogen active ingredient, preferably a mixture


CA 02462075 2004-03-26
7
of natural conjugated equine estrogens in an amount of 0.05 mg to 10 mg
depending on the type of estrone used, and the combined daily dosage
unit contains the estrogen active ingredient, preferably also a mixture
of natural conjugated equine estrogens, in an amount of 0.05 mg to
mg, depending on the type of estrone used, and contains the gestagen
active ingredient in an amount of 0.05 mg to 50 mg, depending on the
type of gestagen used. Medrogestone, which is the preferred gestagen
for use here, is present in an amount of 1 mg to 20 mg, in particular
in an amount of 1 mg to 10 mg. Those skilled in the art will be
familiar with the quantities to be used for the particular individual
estrogen and/or gestagen active ingredients.
In an especially preferred variant of this invention, the daily
dosage unit of the estrogen active ingredient contains 14 mg of an
extract from the urine of gravid mares standardized to 0.33 mg sodium
salt of estrone 3-hydrogen sulfate and 0.17 mg sodium salt of equiline
3-hydrogen sulfate (corresponding to 0.6 mg conjugated equine
estrogens) and the combined daily dosage unit consists of a combination
of 14 mg of an extract from the urine of gravid mares standardized to
0.33 mg sodium salt of estrone 3-hydrogen sulfate and 0.17 mg sodium
salt of equiline 3-hydrogen sulfate (corresponding to 0.6 mg conjugated
estrogens) as the estrogen active ingredient and another 5 mg
medrogestone as the gestagen active ingredient.
The active ingredients are in the daily dosage units where they
are mixed in a suitable manner with the conventional pharmaceutical
vehicles and excipients, for example, as an orally administerable solid
galenical formulation, e.g., as tablets, pills or coated pills in any
geometric design in particular. To produce these solid oral
pharmaceutical forms, the usual galenical preparation methods may be
used, including in addition to tableting or pill production methods, if
desired, film coating methods and pill coating methods. Those skilled
in the art will be familiar with these methods. For example the
pharmaceutical materials known in the related art may be considered for
the pharmaceutical vehicles and excipients such as the usual organic
and/or inorganic vehicle substances such as lactose, talc or starch,
for example, and other excipients that are conventionally used
pharmaceutically as needed such as matrix forming substances, binders,


CA 02462075 2004-03-26
8
granulation aids, lubricants, slip agents, humectants or desiccants,
fillers, coloring agents or tablet disintegrants. In addition other
excipients may also be added such as preservatives, stabilizers, taste
correcting agents, flavoring agents and the like. Sheathed solid forms
of administration may be in the form of film tablets (film or varnish
tablet), optionally with an additional pill coating layer or as
traditional coated pills. Film tablets here are usually sheathed with a
polymer film. Formulations for sheathing film tablets include for
example plasticizers, dispersion aids or smoothing aids, covering
agents and coloring agents, for example, in addition to the polymer
film-forming agent; the ingredients are usually combined with a
solvent, usually ethanol or acetone, for application to the tablet core
or pill core. Coated pills are usually the solid form of administration
sheathed with a sugar. Pill coating syrup, i.e., highly concentrated
sugar solutions with a sugar content of up to 80 wt~ are generally used
for pill coating. Sucrose is the main sugar used here. Different layers
are applied one after the other and in portions to a core in the
essentially known pill coating methods, e.g., the cover layer of a few
portions of syrup coating and powder coating dispersed in between; the
application layer of multiple portions of application syrup and
application powder dispersed in between; a smoothing layer of pure
syrup, possibly colored, to impart a brilliance to the pill surface;
followed by glazing or polishing with a wax or a wax solution as the
final step.
Examples of vehicles and excipients that can be used include
inert inorganic materials such as tribasic calcium phosphate, calcium
sulfates or titanium dioxide or inert organic materials such as
carnauba wax, cellulose, glycerol monooleate, lactose, magnesium
stearate, methyl cellulose, pharmaceutical glaze, polyethylene glycol,
stearic acid, sucrose. Preferred oral pharmaceutical preparations
according to the present invention include for example materials such
as gum arabic, carmellose sodium, carnauba wax, lactose, Macrogol 4000
and 6000, magnesium oxide, magnesium stearate, cornstarch, povidone,
sucrose, shellac, talc, bleached wax, coloring agents E104, E127 and
E171.


CA 02462075 2004-03-26
9
The solid oral daily dosage units may also be pigmented, if
desired, e.g., for identification and differentiation of the estrogen
dosage units and combined estrogen-gestagen dosage units. As an
alternative or in addition, the identification and differentiation may,
if desired, also be accomplished via the packaging material in which
the daily dosage units with the estrogen active ingredient on the one
hand and with the combined estrogen-gestagen active ingredients on the
other hand are made available. The dosage units may be identified on
the basis of color and/or number, for example.
Therefore, this invention also relates to packaged pharmaceutical
preparations (package units) which [contain]
- a packaging material in which are accommodated separately 14 daily
dosage units (or an integral multiple thereof) of an estrogen active
ingredient and a corresponding number of a combination of an
estrogen active ingredient with a gestagen active ingredient in
combined daily dosage units, and the daily doses of the estrogen
active ingredient on the one hand and the combined daily doses of
the estrogen active ingredient and the gestagen active ingredient on
the other hand are marked in a suitable manner to clearly
differentiate them from one another, and
- a label and/or a package insert to indicate that the preparation may
be administered for the prevention, relief and/or treatment of
menopausal symptoms in women, especially in women with an intact
uterus when a menstrual cycle is no longer desirable, by
uninterrupted daily administration of the daily dosage units,
alternating each day, of the estrogen active ingredient and the
combined daily dosage units of the combination of the estrogen
active ingredient with the gestagen active ingredient over a period
of at least 28 days (28-day cycle).
In a preferred embodiment, the inventive packaged pharmaceutical
preparation is characterized in that the daily dosage unit with the
estrogen active ingredient on the one hand and the daily combined
dosage unit of the estrogen active ingredient and the gestagen active
ingredient on the other hand are identified by visual marking,


CA 02462075 2004-03-26
preferably by a difference in color to differentiate them from one
another.
In an especially preferred embodiment, the inventive packaged
pharmaceutical preparation includes as the packaging material a blister
pack on which is printed a system for facilitating the alternating
administration of the daily dosage units of the estrogen active
ingredient and the combined daily dosage unit of estrogen active
ingredient and gestagen active ingredient, preferably as a scheme using
integers from 1 to 28 to record the sequence of the particular dosage
units to be administered each day.
To facilitate daily usage of the particular appropriate dosage
unit, they may be presorted alternately in a pill dispenser that is
subdivided into compartments, e.g., for a month (28 days) or they may
be presorted subsequently from a blister pack. This invention therefore
also concerns packaged pharmaceutical preparations as the package units
which [contain]
- a packaging material accommodating separately 14 daily dosage units
(or an integral multiple thereof) of an estrogen active ingredient
and the corresponding number of a combination of an estrogen active
ingredient with a gestagen active ingredient in combined daily
dosage units, and the daily doses of the estrogen active ingredient
on the one hand and the combined daily doses of the estrogen active
ingredient and the gestagen active ingredient on the other hand are
labeled in a suitable manner to clearly differentiate one from the
other, and
- a label and/or a package insert to indicate that the preparation may
be administered for the prevention, relief and/or treatment of
menopausal symptoms in women, especially in women with an intact
uterus when a menstrual cycle is no longer desirable, by
uninterrupted daily administration of the daily dosage units,
alternating each day, of the estrogen active ingredient and the
combined daily dosage units of the combination of the estrogen
active ingredient with the gestagen active ingredient over a period
of at least 28 days.


CA 02462075 2004-03-26
11
In a preferred embodiment, the inventive packaged pharmaceutical
preparation described above is characterized in that the packaging
material is a pill dispenser subdivided into 28 compartments,
preferably a pill dispenser subdivided into 28 compartments with these
compartments arranged in a ring accommodating a daily dosage unit of an
estrogen active ingredient which alternates with a combined daily
dosage unit of an estrogen active ingredient and a gestagen active
ingredient, with the dosage units labeled appropriately so that they
are clearly differentiable.
If desired, the individual compartments may be labeled by the
days of the week, thereby supplementing the color labeling of the
dosage units.
Blister packs are expediently produced as the packaging material
for distribution of the pharmaceutical preparation and the pill
dispensers described above are only distributed along with the blister
pack as a supportive measure.
As an alternative to the alternating treatment regimen described
for the inventive preparations, the gestagen may also be administered
according to a traditional cyclic treatment regimen which may if
desired also be printed on a front side of the blister pack for example
in addition to the alternating treatment regimen as an option for
selection given on the back side of the blister pack. The packaged
pharmaceutical preparations may thus provide two different treatment
regimens, e.g., on a blister pack and the user may select between the
two dosage regimens provided, whereby the treating physician decides at
the start of treatment which of the two regimens is suitable for the
patient in question. The cyclic treatment regimen which is additionally
provided, optionally as a selection option is suitable in particular
for female patients who still are having regular menstrual periods and
would like to continue to do so. The gestagen is administered
cyclically here, e.g., as shown in an exemplary embodiment in FIG 2;
other embodiments are also conceivable. For example if the estrogen
active ingredient is formulated in white pills and the estrogen-
gestagen active ingredient combination is formulated in pink pills,
then the alternating administration of gestagen is accomplished by


CA 02462075 2004-03-26
12
administered one white pill daily from day 1 through day 14 of the
cycle and one pink pill daily from day 15 through day 28 of the cycle.
In this cyclic dosage regimen, the pills are to be taken
according to a treatment regimen printed on the front side of a blister
pack strip, beginning at the starting point and continuing in the order
of the arrows, as illustrated in the embodiment shown as an example in
FIG 2, for example. In the case of inventive embodiments of a blister
pack according to FIG 3 or FIG 4, for example, the selection option of
the traditional cyclic treatment regimen may be printed on the front
side of the blister pack, e.g., according to the arrangement of the
particular pills and likewise indicated by arrows or numbers.
After the (pills in the] blister pack have been used up, i.e.,
after conclusion of a 28-day cycle, administration is resumed with a
new blister pack according to the same cyclic treatment regimen on the
following day, i.e., without a pause in usage, as described above,
following the arrows that are used for orientation.
If the patient has still been having regular monthly periods
before the start of the treatment, the first dose is taken on day 1 of
her menstrual cycle or when changing to the dosage regimen. Women who
no longer have a uterus or who are no longer having a menstrual cycle
can begin taking the medication at any time.
A special advantage of this invention, in particular the packaged
pharmaceutical preparations, is that patient compliance with the
treatment is greatly increased due to the form of administration. This
is true in particular of the packaged pharmaceutical preparations which
are designed so that they also allow a traditional cyclic treatment
regimen in addition to the alternating treatment according to this
invention as a selection option because it is possible to avoid a
change in preparations when switching from one treatment regimen to the
other. Therefore, the patients affected by such a switch can continue
to take the preparation in the usual formulation which has proven to be
tolerated individually well and with a switch it is possible to prevent
from the beginning any intolerance which might otherwise occur.
Explanation of the Figures


CA 02462075 2004-03-26
13
FIG 1: Blister pack according to this invention with an imprint of
the dosage regimen (back side of the blister pack);
numerical scheme.
FIG 2: Front side of the blister pack with an alternative dosage
regiment fox the case when menstrual bleeding is still
desired; arrow scheme.
FIG 3: Blister pack according to this invention with a dosage
regimen printout (back side of the blister pack); numerical
scheme.
FIG 4: Front side of the blister pack with a dosage regimen
printout according to this invention; arrow scheme.
FIG 5: FIG 5A - pill dispenser without contents; FIG 5B - pill
dispenser with contents.
The following example is presented to illustrate this invention
on the basis of a concrete pharmaceutical preparation although without
limiting the scope of this invention.
Example
An example of a package unit (packaged pharmaceutical
preparation) contains the combination preparation consisting of the two
different hormone pills, namely white pills containing an estrogen
active ingredient and pink pills containing an estrogen and a gestagen.
The estrogen content is obtained as a standardized extract from the
urine of gravid mares. The gestagen component (corpus luteum hormone
content) consists of medrogestone. One package unit contains 14 white
pills and 14 pink pills.
One white pill contains as the active pharmaceutical ingredients
14 mg of an extract from the urine of gravid mares, standardized to
0.33 mg sodium salt of estrone 3-hydrogen sulfate and 0.17 mg sodium
salt of equiline 3-hydrogen sulfate (corresponding to 0.6 mg conjugated
equine estrogens).
One pink pill contains as the active pharmaceutical ingredients
14 mg of an extract from the urine of gravid mares, standardized to
0.33 mg sodium salt of estrone 3-hydrogen sulfate and 0.17 mg sodium


CA 02462075 2004-03-26
14
salt of equiline 3-hydrogen sulfate (corresponding to 0.6 mg conjugated
estrogens) and 5 mg medrogestone.
Other ingredients in both pills (white and pink): gum arabic,
carmellose sodium, carnauba wax, lactose, Macrogol 4000 and 6000,
magnesium oxide, magnesium stearate, cornstarch, povidone, sucrose,
shellac, talc, bleached wax, coloring agents E104, E127 and E171.
Packaged pharmaceutical preparations may have the following form
of administration and content, for example:
(a) Pills in a package containing a total of 28 pills (one-month
package for a 28-day cycle; 14 white pills and 14 pink pills); or
(b) Pills in a package containing a total of 84 pills (quarter-year
package with 3 x 28 pills for three 28-day cycles; 3 x 14 white
pills and 3 x 14 pink pills).

Representative Drawing

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Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2002-09-25
(87) PCT Publication Date 2003-04-10
(85) National Entry 2004-03-26
Examination Requested 2004-03-26
Dead Application 2008-09-25

Abandonment History

Abandonment Date Reason Reinstatement Date
2005-09-26 FAILURE TO PAY APPLICATION MAINTENANCE FEE 2006-01-17
2007-09-25 FAILURE TO PAY APPLICATION MAINTENANCE FEE
2007-12-20 R30(2) - Failure to Respond
2008-02-06 FAILURE TO RESPOND TO OFFICE LETTER

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $800.00 2004-03-26
Application Fee $400.00 2004-03-26
Maintenance Fee - Application - New Act 2 2004-09-27 $100.00 2004-03-26
Extension of Time $200.00 2005-06-29
Reinstatement: Failure to Pay Application Maintenance Fees $200.00 2006-01-17
Maintenance Fee - Application - New Act 3 2005-09-26 $100.00 2006-01-17
Extension of Time $200.00 2006-06-29
Maintenance Fee - Application - New Act 4 2006-09-25 $100.00 2006-08-04
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
SCHWANITZ, DIETHARD
ROGOLL, JUTTA
HACHMEISTER, BERND
Past Owners on Record
None
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Abstract 2004-03-26 1 6
Claims 2004-03-26 4 157
Description 2004-03-26 14 661
Drawings 2004-03-26 3 197
Cover Page 2004-05-27 1 26
PCT 2004-03-26 4 149
Assignment 2004-03-26 4 116
Correspondence 2004-03-29 17 1,343
Prosecution-Amendment 2004-03-26 1 36
Correspondence 2004-05-25 1 31
Prosecution-Amendment 2004-05-26 3 195
Correspondence 2005-06-29 2 43
Correspondence 2005-07-15 1 17
Fees 2006-01-17 1 43
Correspondence 2006-06-29 1 45
Correspondence 2006-07-20 1 17
Prosecution-Amendment 2007-06-20 2 64
Correspondence 2007-11-06 1 30